SYNTHESIS OF ISOWETHADONE
Nov. 20, 1952 [CONTRIBUTION FROM
THE
5619
RESEARCH LABORATORIES OF MERCK & Co., INC.]
The Synthesis of Isornethadone BY MEYERSLETZINGER, EARLM. CHAMBERLIN AND MAXTISHLER RECEIVED JUNE 23, 1952 Two new and direct syntheses of isomethadone are described. In these methods diphenylacetonitrile is alkylated with 1methylformamido-2-chloropropaneand with the tosyl ester of 1-chloropropanol-2 to give, respectively, 4-methylformamido2,2-diphenyl-3-methylbutanenitrile (IV) and 4-chloromethyl-2,2-diphenyl-3-methylbutanenitrile (VIII). These nitriles are readily converted into isornethadone.
In view of the importance of isomethadone (I),
G-dimethylamino-5-methyl-4,4-diphenyl-3 -hexanone, as an analgesic,' i t was of interest to investigate simpler methods of synthesis. Hitherto, isomethadone has been prepared only as a by-product of the methadone synthesis and, in fact, major attention has been devoted to the synthesis of the latter a t the expense of its isomer.2 In this synthesis, diphenylacetonitrile is alkylated with l-dimethylamino-2-chloropropane giving rise to a mixture of 2,2-diphenyl-4-dimethylaminovaleronitrile (11) and 4 - dimethylamino - 2,2 - diphenyl - 3 - methylbutyronitrile (111). The isomeric nitriles are converted to methadone (IV) and isomethadone, respectively, by reaction with ethylmagnesium bromide. The formation of the two nitriles in the alkylation reaction is believed to be due to the cyclic quaternary structure of the alkylating agent.a
v using sodamide in toluene 4-chloromethyl-2,2diphenyl-3-methylbutanenitrile (VI) is formed in a t least 65% yield. No isomeric nitrile could be isolated from the reaction mixture. The chloro compound VI was readily converted to the desired nitrile I11 by reaction with dimethylamine a t 150". CH,CHCHzCl
I
(C6Hj)zCHCN ______)
OSOZC~HICH,
Na"z
(CsHj)zC--Cx
I
(CH8)zXH
-e- 111
CH3CHCHzCl VI 7
+
( ~ ~ 1 1cx~ ) ~ ~ ( c ~ H ~ ) ~ c - c N
I
CIIzCHCIls
I
\
(CHa)zNCHzCH-CIIa
in1
N(cH~)~ I1
/ (C ~ H ~ ) ~ C C O C H Z C H ~
I
CHzCHCIIj
IV
I
N(C&)z
(C&Ij)zCCOCHzCHa
I
(CIla)ziYCHzCHCI-I3
I
Two new syntheses of isomethadone have been realized. In the first, diphenylacetonitrile is alkylated with 1-methylformamido - 2 - chloropropane which reacts normally in displacement reactions. The resulting formamide V is readily reduced with a mixture of formic acid and formaldehyde to the desired butyronitrile 111. The second approach utilizes the greater reactivity of a secondary tosyl ester in comparison with a primary chlorine atom in alkylation reactions. Thus, in the alkylation of diphenylacetonitrile with the tosyl ester of 1-chloropropanol-2
Two other sulfonic esters of 1-chloro-2-propanol were used in the alkylation of diphenylacetonitrile. The benzenesulfonyl and the methanesulfonyl esters gave, respectively, 60 and 53% yields of the chlorobutyronitrile VI. The preparation of the chloronitrile VI by alkylation of diphenylacetonitrile with 1-chloro-2-bromopropane was reported previously4 in good yields (70%). However, the reaction of this compound with morpholine to give the corresponding morpholinobutyronitrile proceeded poorly (18% yield). The identity of the butyronitrile I11 obtained from these syntheses was established by comparing melting points of the picrates and the p-toluenesulfonates with authentic samples and by examination of infrared spectra. Identity was further confirmed by conversion to isomethadone. Acknowledgment.-The authors wish to express their thanks to Dr. Nelson Trenner for the infrared absorption data, to hfr. Richard Boos for the analytical data, and to hIessrs. William Martin and Henry W. Johnson for technical assistance. Experimental
All melting points are uncorrectcd. 1-Methylformamido-2-propanol.-A m i x t t ~ r eof 89 g. of 1-methylamino-2-propanol and 180 g. of formamide was (1) K. K.Chen, A m . N. Y.Acod. Sci., 61, 94 (1948); U.S.Armed Forces Medical Journal, I, 1269 (1951). heated with stirring a t 150-160' for 3 hours. The mixture was cooled and fractionated using a Vigreux column. The (2) Office of Publications Board, Dept. of Commerce, Report P. B. 981, p. 96-A; E. M. Schultz. C. M. Robb and J. M . Sprague. THIS first fraction boiling a t 63-71' (1 mm.) and weighing 136.0 JOURNAL, 69, 188,2454 (1947): N.R.Baston, J. H. Gardner and J. R. g. was practically pure formamid?. The second and third Stevens, ibid., 69, 976 (1947), 70, 76 (1948); R.H.Thorp, E. Waltoa fractions boiled a t 90-92" ( 5 m m . ) . The yield was 109.4 g. and P. Ofner, NaWrc, 169,679 (1947); E. Walton, P. Ofner and R. H. (93%), nZaD 1.4665. Thorp, J . Chem. SOC.,648 (1949). Anal. Calcd. for CSHUOSS: C, 51.28; H , 9.40; N, (3) W. R. Brode and M. W. Hill, THIS JOURNAL, 69, 724 (1947). 11.96. Found: C, 51.18; H , 9.64; N, 11.91.
E. M.Schultz and J. M. Sprague. ibid., 70, 48 (1948); A. A. Larsen; B. F. Tullar, B. Elpern and S. S. Buck, ibid., 7 0 , 4194 (1948); L. C, Chcney, R. R. Smith and S. B. Binkley, i b i d . , 71, 55 (1949).
(4) J. Attenburrow, J. Elks, B. A. Hems and K. N. Speger, J . Chem. SOC..516 (1949).
l-Methylformamido-2-chloropropane.-To a solution of 109.4 g. of l-1nethylformamido-2-propanol dissolved in 235 cc. of dry chloroform and 56.4 g. of dry pyridine was added with stirring 89.6 g. of thiouyl chloride ov$r a period of 30 minutes, keeping the temperature below 73 . The reaction mixture was maintained a t 73' for 10 hours and then cooled io room temperature. The mixture was washed with saturated sodium chloride solution and then with saturated sodium bicarbonate, and finally with water. The organic layer was dried over sodium sulfate, the solvent removed i n DUCUO and distilled; yield 77 g. (79%), h.p. 139-141' ~ (58 mm.), n Z p . 51.4699. Anal Calcd. for CsHl&lSO: C , 44 28; H, 7 40; N, 10.:33; C1, 26 15 Found: C, 44.49; €1, 7.70; N , 10 28; CI, 25.88.
ture was diluted with 300 cc. of ethcr or benzene, washed successively with 2.5 N HCI, water, 1 N sodium hydroxide and finally with water. The washed solution was dried over anhydrous magnesium sulfate, concentrated in vacuo and the crude ester was distilled, b.p. 119-120" at 0.05 mm.; yield 227 g. (91%). Anal. Calcd. for Cl~H~:j03C1S: C1, 14.26. Found: CI, 13.9. In a similar manner the esters of benzenesulfonic acid (yield 87%, b.p. 105-106' (0.1 mm.))and methanesulfonic acid (yield 75%; b.p. 76-77' (0.4 mm.)) were prepared. 4-Chloromethyl-2,2-diphenyl-3-methylbutanenitrile (VI). -----L)iphenylacetonitrile,101 g., was dissolved in 800 cc. of dry toluene and added to a slurry of 20.3 g. of sodamide in 200 cc. of dry toluene. The mixture was heated with stir4-Methylformamido-2,2-diphenyl-3-methylbutanenitrilering t o 106' under nitrogen. Heating and stirring was (V).-To a solution of 19.3 g. of diphenylacetonitrile dis- continued until 95% or more of the theoretical amount of solved in 40 cc. of xylene was added 3.9 g. of sodamide ammonia was evolved. The reaction mixture was cooled slurried in 35 cc. of xylene. The mixture was heated with to 65", and 130 g. of p-toluenesulfonate ester VI1 was added stirring under a nitrogen atmosphere t o 105-110° until the slowly with stirring keeping the temperature below 80". The reaction mixture was heated at reflux with stirring for quantitative amount of ammonia had been liberated. lcniperaturc of the reaction inixturc was brought t o Thz 30 18 hours, cooled t o room temperature and poured into 500 and 0.27 g. of sodium iodide added, followed by the drop- 1111. of water. The organic layer was washed with water, wisc addition over a period of 15 minutes of 6.8 g. of 1- dried over anhydrous magnesium sufate, and concentrated t n vacuo. The residue was distilled, b.p. 119-124' (0.1 ~nethylformamido-2-chloropropane. During the addition the temperature rose t o 35". The reaction mixture was mm.); yield, 160 g., 65'%. heated to 110-115" for 3 hours, cooled to room temperature d4nal. Calcd. for CITHI~NCI:C, 75.68; H, 5.98; S , and extracted with watcr. The aqueous solution was ex- 5.19. Found: C , 75.68; H , 5.90; N, 5.33. tracted with benzene. The organic layers were combined, filtered from a small amount of insoluble material and con- (III).-A4-Dimethylamino-2,2-diphenyl-3-methylbutanenitrile Carius bomb tube was charged with 25 g. of the centrated t o dryness it2 vacuo. The residue was dissolved chloronitrile V I I I , 25 cc. of anhydrous dimethylamine and in 100 cc. of ether and cooled overnight at 55-10' to obtain 0.5 g. of copper sulfate. The sealed tube was heated for a crystalline product, 8.4 g. (57.5%), m.p. 127.5-129'. 48 hours at 150". The reaction mixture was cooled to For analysis the product was recrystallized from butanol. room temperature and extracted with benzene. The benAnal. Calcd. for ClvHzoNrO: C, 78.08; 13, 8.84; N, zene extract was washed with water and then extracted with 9.6:j. Found: C, 78 31; H, 7.06; N , 9.68. 2.5 AT HCI. The acidic extracts were made alkaline and ex4-Dimethylamino-Z,Z-diphenyl-3-methylbutanenitrile tracted with benzene. The benzene extracts were concen(III).-Two grams of trioxane, 6.0 g. of formic acid (98trated in vacuo to an oil which crystallized on standing; yield 100'%) and 5.84 g. of formamido compound ( V ) were heated 14.5 g. (58%). Recrystallization from petroleum ether gave under reflux for 112 hou . At the end of this time a drop a solid which meoted a t 65.5-66.5'. The hydrochloride of the reaction mixture hen added t o an excess of water melted a t 218-220 . A mixed melting point with an authengave a clear solution, indicating a complete reaction. The tic samplc of the nitrile hydrochloride melted a t 218-220". A comparison of the infrared spectra of the nitrile hydromixture was cooled to 25', poured into 100 cc. of water and niade basic with concd. ammonia. The product which chloride with a n authentic sample confirmed the identity separated crystallized completely on standing overnight. of the two compounds. RecrystallizaThe yield was 5.1 g. (91%), m.p. 63-64.5'. Anal. Calcd. for C2gH&2.HC1: C, 72.48; H, 7.36; tion from petroleum ether gave a solid melting a t 65.5S , 8.90. Found: C, 72.34; H, 7.24; X, 9.09. 66.5". A mixed melting point with an authentic sample of 6-Dimethylamino-4,4-diphenyl-5-methyl-3-hexanone (I). m.p. 65.5-66.5" gave no depression. The picrate, m.p. I11 synthesized from synthetic approaches 210-211", and p-tolucnesulfonatc, m.p. 222-224", were also -Compound discussed abovc was converted to isomethadone by orthosynthesized. The mixed melting points of both salts with dox procedure3 and identified by comparison with derivaauthentic samples showed no depression. tives synthesized from an authentic sample. A discussior; . 4 ~ a l . Calcd. for Clllln2S2:. C, 81.97; €1, 7.Cli; S, of the preparation of derivatives is given by Easton, et n2.10.01. Found: C, 81.70; €1, T.82; S, 10.16. The following is a tabulation of data. p-Toluenesulfonate of I-Chloro-2-propanol.-To a mixThe melting point of the picrate was 149-150'. A mixed chloride and 158.2 g. iiielting point with an authentic sample showed no deprcsture of 190.6 g . of p-tc~lucnesulfon~-l of pyridine cooled t o 0 , 94.6 g. of propylene chlorohydrin sion. The melting point of methiodide was 263-264'. as added with stirring over :I period of 20 minutes. Stir- The mixed melting point with an authentic sample exhibited ring at 0" was continued for 1 hour and the reaction mixture n o depression, placed in the ice-box ovcrnight. The reaction mixture was Anal. Calcd. for the monohydrate hydrochloride GIstirred at room temperature for 24 hours. The precipitated HzsNOC1.HrO: C, 69.38; H , 8.31; S , 3.87. Found: C, Iiyridinc hydrochloridc was thcn filtered off. Ten cubic 69.55; H,8.28; N, 4.03. centimeters of water was :tddccl to the cooled filtrate and it \vas then allo~vcd tu i t a i i t l for 1 hour. Tlic rcactioii mix-
